The long-term goal of this research project is to better understand the role of melatonin derived from the pineal gland, in conjunction with phytomelatonin ingested in the diet, in the prevention of the growth of human malignancies in the context of biological timing. Melatonin inhibition of tissue-isolated tumor (rat hepatoma 7288CTC) growth in vivo occurs via inhibitory G protein-coupled melatonin receptor-mediated suppression of cAMP and a resultant blockade of tumor linoleic acid (LA) uptake and 13-hydroxyoctadecadienoic acid (13-HODE). This occurs via inhibition of fatty acid transport protein (FATP) function. 13-HODE, which amplifies the epidermal growth factor EGF-mitogenic signaling pathway, is the mitogenic signal responsible for LA-dependent tumor growth. The hypothesis to be tested is: Melatonin, derived from the pineal gland and dietary sources, plays a significant role in the prevention of human tumor development and growth; the mechanism of action is via melatonin receptor-mediated suppression of cAMP-dependent FATP function and/or expression leading to a blockade of tumor LA uptake and production of 13-HODE in the context of circadian time structure. The first aim is to assess the effects of dietary melatonin on tissue-isolated human tumor growth and LA metabolism in vivo. The second aim is to further define the melatonin signal transduction mechanisms involved in the regulation of tissue-isolated tumor LA metabolism and growth in vivo. The third aim is to examine the interactions among FATP function, melatonin inhibitory signaling, and EGF stimulatory signaling in the control of tissue-isolated tumor LA metabolism and growth. The fourth aim is to further define the circadian rhythm regulation of FA metabolism simultaneously in tissue-isolated tumors and contralateral fat pads and the role of melatonin. The proposed studies will help to provide a scientific rationale for the development of new dietary recommendations that consider LA intake, circadian-timed melatonin supplementation and/or photoperiodic alterations for the prevention and treatment of cancer growth and cachexia.